A novel activating somatic mutation in EPAS1, coding for HIF-2α, in a patient with a paraganglioma and sickle cell disease

Abstract Pheochromocytomasand paragangliomas (collectively referred as PPGLs) are highly heritable neoplasms arise from chromaffin cells of neural crest tissues; 40% of patients with PPGLs harbour germline pathogenic variants (PV), which up to 45% of patients exhibit somatic mutations in similar susceptibility genes. Endothelial PAS domain-containing protein-1 [also known as hypoxia inducible factor-2α, HIF-2α] is encoded by EPAS1, and along with other hypoxia-inducible factors (HIFs) acts as a key mediator in the cellular response to hypoxia. Gain-of-function mutations in EPAS1 have been linked to the Pacak-Zhuang syndrome, congenital cyanotic heart disease and sickle cell anaemia. Hypoxia due to chronic anaemia and/or associated nephropathy in patients with sickle cell disease (SCD) may increase the expression of genes related to HIFs, thereby increasing susceptibility to the development of PPGLs. We describe a case of young female with a history of sickle cell anaemia and sickle cell nephropathy who was found to have a para-aortic mass. Histology confirmed the diagnosis of a paraganglioma. She did not exhibit somatic mutations of the common predisposition genes but demonstrated a likely pathogenic activating somatic EPAS1 variant mutation. This case illustrates the predisposition of patients with SCD to PPGLs due to somatic EPAS1 mutations, and should increase awareness of such tumours in these patients.